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Published on: May 15, 2019
A phenylphthalimide derivative, TC11, induces apoptosis by degrading MCL1 in multiple myeloma cells
Daiju Ichikawa1, Misa Nakamura1, Wakana Murota1
1Division of Clinical Physiology and Therapeutics, Faculty of Pharmacy, Keio University, Minato-ku, Tokyo, Japan.
Abstract:
To date, the prognosis of multiple myeloma (MM) in patients harboring cytogenetic abnormalities (CA) involving t (4; 14) and deletion of chromosome 17 remains poor despite recent advances in drug development that include the use of immunomodulatory drugs (IMiDs) such as lenalidomide for MM. To address this issue, we have developed a novel phenylphthalimide derivative, TC11, that is structurally related to IMiDs. It remains unclear how TC11 induces apoptosis of MM cells with high-risk CA. Here, we show that TC11 does not induce degradation of CRBN's substrates, IKZF1/3 and CK1α, and induces apoptosis of CRBN-silenced MM; this effect was independent of the cereblon (CRBN) pathway, which is involved in the mechanism of action of IMiDs used for the treatment of MM. We also revealed that TC11, in contrast to existing IMiDs, induced degradation of MCL1 and activation of caspase-9. Furthermore, inhibition of CDK1 by CGP74514A prevented TC11-induced MCL1 degradation, caspase-9 activation, and the subsequent apoptotic cell death. We showed that ectopic MCL1 expression rescued apoptosis of MM. These observations suggest that TC11 induces apoptotic death caused by degradation of MCL1 during prolonged mitotic arrest. Therefore, our findings suggest that TC11 is a potential drug candidate for high-risk MM.
Insights
A novel compound, TC11, effectively targets high-risk multiple myeloma (MM) by degrading MCL1, independent of the cereblon (CRBN) pathway. This offers a new therapeutic strategy for patients with poor prognoses.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Multiple myeloma (MM) with specific cytogenetic abnormalities (CA), such as t(4;14) and chromosome 17 deletion, has a poor prognosis.
- Current treatments, including immunomodulatory drugs (IMiDs), show limited efficacy in these high-risk MM patients.
Purpose of the Study:
- To investigate the mechanism of action of a novel phenylphthalimide derivative, TC11, in high-risk MM cells.
- To determine if TC11's efficacy is dependent on the cereblon (CRBN) pathway, unlike existing IMiDs.
Main Methods:
- TC11's effect on CRBN substrate degradation (IKZF1/3, CK1α) and apoptosis in CRBN-silenced MM cells was assessed.
- MCL1 degradation, caspase-9 activation, and cell death induction by TC11 were analyzed.
- The role of CDK1 inhibition and ectopic MCL1 expression in TC11's apoptotic effects was investigated.
Main Results:
- TC11 induced apoptosis in MM cells independently of the CRBN pathway.
- TC11 triggered MCL1 degradation and caspase-9 activation, distinct from IMiD mechanisms.
- CDK1 inhibition blocked TC11-induced apoptosis, while MCL1 overexpression rescued it.
Conclusions:
- TC11 induces apoptosis in high-risk MM by degrading MCL1, leading to prolonged mitotic arrest.
- TC11 represents a promising therapeutic candidate for multiple myeloma patients with poor-prognosis cytogenetic abnormalities.
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